Early astrocyte redistribution in the optic nerve precedes axonopathy in the DBA/2J mouse model of glaucoma

Melissa L. Cooper, Samuel D. Crish, Denise Maureen Inman, Philip J. Horner, David J. Calkins

Research output: Contribution to journalArticle

23 Citations (Scopus)

Abstract

Glaucoma challenges the survival of retinal ganglion cell axons in the optic nerve through processes dependent on both aging and ocular pressure. Relevant stressors likely include complex interplay between axons and astrocytes, both in the retina and optic nerve. In the DBA/2J mouse model of pigmentary glaucoma, early progression involves axonopathy characterized by loss of functional transport prior to outright degeneration. Here we describe novel features of early pathogenesis in the DBA/2J nerve. With age the cross-sectional area of the nerve increases; this is associated generally with diminished axon packing density and survival and increased glial coverage of the nerve. However, for nerves with the highest axon density, as the nerve expands mean cross-sectional axon area enlarges as well. This early expansion was marked by disorganized axoplasm and accumulation of hyperphosphorylated neurofilamants indicative of axonopathy. Axon expansion occurs without loss up to a critical threshold for size (about 0.45–0.50 μm2), above which additional expansion tightly correlates with frank loss of axons. As well, early axon expansion prior to degeneration is concurrent with decreased astrocyte ramification with redistribution of processes towards the nerve edge. As axons expand beyond the critical threshold for loss, glial area resumes an even distribution from the center to edge of the nerve. We also found that early axon expansion is accompanied by reduced numbers of mitochondria per unit area in the nerve. Finally, our data indicate that both IOP and nerve expansion are associated with axon enlargement and reduced axon density for aged nerves. Collectively, our data support the hypothesis that diminished bioenergetic resources in conjunction with early nerve and glial remodeling could be a primary inducer of progression of axon pathology in glaucoma.

Original languageEnglish
Pages (from-to)22-33
Number of pages12
JournalExperimental eye research
Volume150
DOIs
StatePublished - 1 Sep 2016

Fingerprint

Inbred DBA Mouse
Optic Nerve
Astrocytes
Glaucoma
Axons
Neuroglia
Nerve Expansion
Retinal Ganglion Cells
Open Angle Glaucoma
Energy Metabolism
Retina
Mitochondria

Keywords

  • Astrocyte
  • Axonopathy
  • Glaucoma
  • Gliosis
  • Neurodegeneration
  • Retinal ganglion cell

Cite this

Cooper, Melissa L. ; Crish, Samuel D. ; Inman, Denise Maureen ; Horner, Philip J. ; Calkins, David J. / Early astrocyte redistribution in the optic nerve precedes axonopathy in the DBA/2J mouse model of glaucoma. In: Experimental eye research. 2016 ; Vol. 150. pp. 22-33.
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Early astrocyte redistribution in the optic nerve precedes axonopathy in the DBA/2J mouse model of glaucoma. / Cooper, Melissa L.; Crish, Samuel D.; Inman, Denise Maureen; Horner, Philip J.; Calkins, David J.

In: Experimental eye research, Vol. 150, 01.09.2016, p. 22-33.

Research output: Contribution to journalArticle

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AU - Cooper, Melissa L.

AU - Crish, Samuel D.

AU - Inman, Denise Maureen

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AU - Calkins, David J.

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AB - Glaucoma challenges the survival of retinal ganglion cell axons in the optic nerve through processes dependent on both aging and ocular pressure. Relevant stressors likely include complex interplay between axons and astrocytes, both in the retina and optic nerve. In the DBA/2J mouse model of pigmentary glaucoma, early progression involves axonopathy characterized by loss of functional transport prior to outright degeneration. Here we describe novel features of early pathogenesis in the DBA/2J nerve. With age the cross-sectional area of the nerve increases; this is associated generally with diminished axon packing density and survival and increased glial coverage of the nerve. However, for nerves with the highest axon density, as the nerve expands mean cross-sectional axon area enlarges as well. This early expansion was marked by disorganized axoplasm and accumulation of hyperphosphorylated neurofilamants indicative of axonopathy. Axon expansion occurs without loss up to a critical threshold for size (about 0.45–0.50 μm2), above which additional expansion tightly correlates with frank loss of axons. As well, early axon expansion prior to degeneration is concurrent with decreased astrocyte ramification with redistribution of processes towards the nerve edge. As axons expand beyond the critical threshold for loss, glial area resumes an even distribution from the center to edge of the nerve. We also found that early axon expansion is accompanied by reduced numbers of mitochondria per unit area in the nerve. Finally, our data indicate that both IOP and nerve expansion are associated with axon enlargement and reduced axon density for aged nerves. Collectively, our data support the hypothesis that diminished bioenergetic resources in conjunction with early nerve and glial remodeling could be a primary inducer of progression of axon pathology in glaucoma.

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